Effects of cobalt sulfate on prenatal development of mice, rats, and rabbits, and on early postnatal development of rats.

The effects of cobalt sulfate administered to pregnant C57BI mice, OFA-SD rats, and New Zealand rabbits was studied on fetal and postnatal offspring. Cobalt concentration in the maternal blood was increased in proportion to the administered doses. Cobalt crossed the placenta and appeared in the fetal blood and amniotic fluid. Regardless of the administered dose of cobalt sulfate, cobalt concentration in the blood peaked 2 h after administration. Cobalt produced dose-dependent maternal toxicity and was found to be embryotoxic in all three species, as evidenced by elevated frequency of fetuses with body weight or skeletal retardation and embryolethality. Cobalt increased the frequency of major anomalies significantly in mice and rats, with anomalies of the eyes, kidneys, skull, spine, and sternum in mice, and anomalies of the urogenital system in rats. Cobalt sulfate was not teratogenic in rabbits. Intra-amnial administration of cobalt sulfate produced a dose-dependent increase of the frequency of dead fetuses, and weight retardation of the live fetuses. The direct cytotoxic effect probably plays a role in the embryotoxic and teratogenic effects of cobalt. The postnatal examinations revealed a decrease of the perinatal index in the treated group. The body weight of the pups in the treated group was lower during wk 1 of life, but no difference was found between the control and treated by the end of wk 2. Eye opening was completed in the usual time period in both groups, while time of appearance of the teeth, descending of the testes, shaping of ears, and development of hearing was delayed in the treated group. The development of muscle strength and of the locomotor system was delayed. All the functions studied (forward movement, swimming, righting reflex) normalized by postnatal d 21, with the exception of muscle strength. It was concluded that cobalt sulfate exposure decreases the perinatal viability of the fetuses, but the functions of the surviving fetuses with perinatal retardation become compensated by postnatal wk 2-3. The development of fetuses is undisturbed thereafter.

The effect of prenatal indium chloride exposure on chondrogenic ossification.

Daily indium chloride doses of control (0) or 400 mg/kg were administered orally to pregnant Sprague-Dawley (SD) rats by gavage, on d 20 of gestation. Indium concentration was determined in the maternal and fetal blood, livers, kidneys, skulls, and femurs by atomic absorption spectrometry. Further groups of pregnant rats were treated with control (0) or 400 mg/kg indium chloride orally, during the whole gestation period. The fetuses were examined on d 21 of gestation, using histological and histochemical methods. Four hours after the administration indium concentration was found to be significant in the blood, liver, and kidneys of the dams. Twenty-four hours later it increased in the blood but not in the liver and kidney. Fetal indium concentrations were 40-50% of the maternal levels due to a barrier of the placenta. In the skull and the femur, indium was already detectable at 4 h after the administration, and by the end of 24 h, metal concentration was several times higher than that at 4 h, indicating accumulation. Furthermore, it was found that the birefringency of collagen detectable by picrosirius red staining in polarized light around the chondrocytes disappeared and became irregular. In the matrix of the epiphyseal cartilage, the regular, birefringent network demonstrable by Rivanol reaction became irregular and hardly recognizable. In the cytoplasm of the chondrocytes, the diffuse, evenly distributed positive Ricinus communis agglutinin reaction became irregular or disappeared. Similar but much weaker changes were observed with concanavalin A and wheat germ agglutinin stainings. It was concluded that the missing femur and micromelia diagnosed by alizarin staining is the consequence of a specific toxic effect of indium that inhibits chondrogenic ossification. No similar histochemical changes were observed in the bones of the skull developing by desmogenic ossification, despite the presence of indium. Data indicate that the mechanisms of the effects of indium causing retardation and/or malformation differ in the bones developing through desmogenic or chondrogenic ossification.

Hemodynamic effect of indium chloride in pregnant rats.

Daily indium chloride doses of control (0) or 200 mg/kg were administered orally to pregnant Sprague-Dawley (SD) rats by gavage, on d 6-15 of gestation. On d 16 of gestation hemodynamic tests were performed; Arterial blood pressure, cardiac output (CO), and volume organ blood flow were determined with radioactive microspheres using the reference sample method (McDevitt & Nies, 1976). Indium chloride increased the cardiac index (CI), but did not change arterial blood pressure and total peripheral resistance (TPR). Indium decreased the organ fractions of the cardiac output to kidneys, ovaries, uterus, and placenta, while those to brain, lungs, and liver were not affected. In the placenta the blood flow was reduced significantly while the vascular resistance increased. The blood flow and vascular resistance did not change in the rest of the organs studied. The changes in arterial blood pressure, CO, Cl, TPR, organ fraction of cardiac output, blood flow, and vascular resistance in most of the organs displayed normal responsiveness to noradrenaline (NA) infusion. The reduction of uterine and placenta fractions and placental blood flow, produced by NA infusion were significantly greater in control than in the indium-treated group. Data indicate that the hemodynamic changes induced by indium are detrimental to the fetus. Indium chloride exposure modifies the maternal effect of noradrenaline such that there is maternal survival at the expense of fetal mortality.

Embryotoxic and teratogenic effects of indium chloride in rats and rabbits.

Daily indium chloride doses of control (0), 50, 100, 200, or 400 mg/kg were administered orally to Sprague-Dawley rats by gavage, on d 6-15 of gestation, and daily metal doses of control (0), 50, 100, or 200 mg/kg were administered to New Zealand rabbits on d 6-20 of gestation. Further groups of pregnant rats were treated with control (0) or 400 mg/kg indium chloride orally on one of d 8, 9, 10, 11, 12, 13, 14, or 15 of gestation. The dams and fetuses were examined on d 21 (rats) and 30 (rabbits) of gestation, using standard teratological methods. Indium concentration was determined in the maternal and fetal blood, as well as in the amniotic fluid, by atomic absorption spectrometry. Indium was found to cross the placenta and appeared in fetal blood in proportion to the metal concentration of the maternal blood. In the amniotic fluid, indium concentrations remained below the detection limit. In rats, indium chloride produced dose-dependent maternal toxic effects, with a dose of 400 mg/kg inducing embryotoxicity (embryolethality) and teratogenicity. Doses of 200 and 100 mg/kg were embryotoxic (retarding) and teratogenic, causing skeletal and visceral anomalies in addition to external anomalies (rudimentary or missing tail, syndactylia, clubfoot, exencephalia) in rats. In rabbits, 200 mg/kg indium chloride was lethal for the dams and the embryos (some of the animals died, and the number of abortions and full resorptions increased). This dose was found to be teratogenic (caused gross renal anomalies) and increased the frequency of fetuses with skeletal retardation. In rats, the effects of indium chloride causing fetal retardation was found to be independent of exposure time. The teratogenic effects were the highest on d 11 and 12 of gestation, when indium chloride caused gross external malformations. Data suggest that the teratogenic effects of indium chloride can be attributed primarily to a direct cytotoxic action of indium resulting from placental transfer, but the effect is not a selective one, as it appears only in the presence of maternal toxic effects.

Haemodynamic effect of nickel chloride in pregnant rats.

Non-pregnant and pregnant CFY rats were given 3 mg/kg nickel chloride or physiological saline by gavage daily for eight days during days 7-14 of organogenesis. The haemodynamic investigations were carried out using 113Sn labelled microspheres. Nickel concentrations in maternal and fetal blood, as well as in amniotic fluid were determined by atomic absorption spectrophotometry. It was found, that nickel crossed the placenta, appeared in the fetal blood and amniotic fluid, where its concentration depended on the dose given to the pregnant animal and the nickel concentration of the maternal blood. Nickel chloride influenced neither the systemic haemodynamic parameters (arterial blood pressure, total peripheral resistance--TPR, cardiac index) nor the values of the organ (including the placenta) circulation indices, neither in the pregnant nor in the non-pregnant animals. It is concluded that in the pathomechanism of embryotoxicity (causing weight gain retardation) and teratogenicity (causing major anomalies of the uropoietic apparatus) of nickel, demonstrated earlier, the assumed effects of nickel on maternal and placental circulation probably do not play role (as such effects could not be detected). The direct embryo-damaging effect of nickel crossing the placenta (direct cytotoxic effect) may be held responsible for the embryotoxicity and teratogenicity of nickel.

The combined cardiovascular effect of alcohol and noise in rats.

Groups of 20 CFY male rats were made to drink water containing 10% alcohol and 5% sugar or 5% sugar. Half of both groups (10-10 animals) were exposed to 95 dBAeq mixed industrial noise for 3 weeks, 6 hours daily. Haemodynamic measurements were carried out using isotope (57Co) labelled microspheres, which were repeated after the i.v. administration of 30 micrograms/kg/3 min noradrenaline, using a second isotope (113Sn). It was found, that alcohol decreased the cardiac fraction of the cardiac output, the nutritive blood flow of the myocardium and increased the vascular resistance of the adrenals. Noise decreased the lung fraction of the cardiac output and the hepatic blood flow. Interaction between noise and alcohol, inhibiting the effect of alcohol, was demonstrated on the intestinal blood flow, adrenal fraction of cardiac output and testicular vascular resistance. The haemodynamic effects of noradrenaline observed in the control were in several organs more or less modified in the animals treated with alcohol or noise or both. It was concluded that the exposures (alcohol, noise or both) modify the alpha-adrenergic effect of noradrenaline.

The effects of simultaneous alcohol and nickel sulphate poisoning on the cardiovascular system of rats.

Two groups of male OFA rats received 10% ethanol and 5% sugar, or 5% sugar in their drinking-water. One half of each group received 5 mg/kg b.w. daily dose of nickel sulphate in 10 ml of physiological saline by gavage, for three weeks, while the other half of the groups received 10 ml physiological saline. Morphological (light and electron microscopic) and haemodynamic (radioactive microsphere method) examinations were performed. It was found, that alcohol caused decreases of borderline significance of the arterial blood pressure and the nutritive blood flow of the heart, while nickel sulphate significantly increased the arterial blood pressure, the vascular resistance of the kidneys, liver and brain, increased TPR in a tendinous way. Following a simultaneous administration of alcohol and nickel considerably increased the arterial blood pressure (statistically interaction at a level of borderline significance) and caused the appearance of swollen mitochondria and dilated sarcoplasmatic reticulum in the ultrastructure of the heart. It is concluded, that 1. pathomechanism of myocardium-damaging effects of nickel sulphate and alcohol is different; 2. nickel sulphate and alcohol together (at least in a certain dose range) increase the arterial blood pressure.

The effects of simultaneous alcohol and cobalt chloride administration on the cardiovascular system of rats.

CFY male rats received drinking water which contained 10% ethyl alcohol and 5% sugar and were treated with 50 mg/kg daily doses of cobalt chloride for three weeks by gavage. Haemodynamic examinations were carried out using radioactive microspheres. Alcohol caused no significant injury of the structure of the myocardium, while cobalt chloride caused incipient multifocal myocytolysis. Blood pressure and nutritive blood flow of the heart were decreased slightly by alcohol and significantly by cobalt chloride. Alcohol additively increased the effect of cobalt chloride decreasing the nutritive blood flow of the heart. It is suggested, that hypoxia increased by dual exposure is responsible for the aggravating effect of alcohol on the myocardial injury caused by the cobalt salt.

Cytogenetic investigations on children with acute non-lymphocytic leukemia.

Cytogenetic data from 30 children with acute non-lymphocytic leukemia (ANLL) are evaluated in connection with patient's age, morphological type of leukemia and prognosis. In 20 out of 30 patients clonal chromosome aberrations were found. The frequency of chromosome aberrations and the prognostic parameters in the various morphological and age groups proved to be different and no direct relationship could be found in a given group between the frequency of aberrations and the prognosis. A more detailed analysis of data, however, provided some evidence that chromosome aberrations observed at diagnosis had a prognostic value independent of age and the morphological properties of blast cells: the normal karyotype and the pseudodiploidy proved to be of a favorable value but the hyperdiploidy and polyploidy an unfavorable prognostic parameter. Besides the known cytogenetic differences between childhood and adult ANLL, some similarities are also emphasized.

Prognostic factors in acute lymphoid leukaemia of childhood. I. Cytogenetic studies.

The results of chromosonal analysis of bone-marrow cells of 30 children with untreated acute lymphoid leukaemia are reported. On the basis of the modal chromosome number found in the cell clone showing the most frequent aberration, the patients could be classified into hypodiploid, pseudodiploid, hyperploid and normal groups. Pseudodiploidy predicted a poor prognosis while the survival rate of patients with normal or hyperploid chromosome counts was favourable.